American Journal of Epidemiology Advance Access originally published online on August 18, 2006
American Journal of Epidemiology 2006 164(7):624-626; doi:10.1093/aje/kwj261
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Invited Commentary |
Invited Commentary: Clues to the Etiology of Inflammatory Bowel Disease—A Return to John Snow?
From the Department of Medicine, Division of Gastroenterology, McMaster University Medical Centre, Hamilton, Ontario, Canada
Correspondence to Dr. Paul Moayyedi, Department of Medicine, Division of Gastroenterology, McMaster University Medical Centre, 1200 Main Street West, HSC 4W8B, Hamilton, Ontario L8N 3Z5, Canada (e-mail: moayyep{at}mcmaster.ca).
Received for publication October 31, 2005. Accepted for publication March 13, 2006.
Abbreviations: GIS, geographic information systems; IBD, inflammatory bowel disease; Th1, T helper cell type 1; Th2, T helper cell type 2
It has been over 150 years since John Snow observed that a specific outbreak of cholera in a small geographic area of London, United Kingdom, seemed to be associated with a Broad Street water pump (1
). The fall in cholera cases after the pump was padlocked supported his theory that cholera was spread by a waterborne contagious agent. His statistical mapping methods led many to suggest that John Snow is the father of modern epidemiology (2). It is ironic that a technique that led to one of the famous success stories of public health medicine has largely been ignored by clinical epidemiologists.
The increasingly sophisticated environmental information available in databases and the development of statistical packages that will perform complex spatial data analysis has led to a resurgence of interest in geographic information systems (GIS) (3). The paper by Green et al. (4) in this issue of the Journal is an excellent example of the strengths and weaknesses of this approach. Using geographic methods, Green et al. modeled the incidence of Crohn's disease and ulcerative colitis in the province of Manitoba, Canada, for the period 1990–2001. Previous evaluation of Manitoba health insurance databases had revealed that there was geographic clustering of inflammatory bowel disease (IBD) that correlated with higher family income and less frequent Aboriginal origin in Canadian populations (5). Green et al. have extended those findings using smaller geographic areas, evaluating a wider range of factors associated with IBD and employing more sophisticated statistical techniques. They report that IBD incidence rates in a small geographic area were associated with higher socioeconomic status and were inversely associated with rates of enteric infection reported in that locale. There was also an association between IBD and incidence rates of multiple sclerosis, suggesting that common environmental factors may be involved in the pathogenesis of both diseases. Green et al. conclude that these data support the "hygiene hypothesis," which posits that early exposure to infection protects against future IBD and development of multiple sclerosis.
The hygiene hypothesis was first proposed in 1989 as a mechanism to explain the increase in allergic diseases seen in industrialized nations (6). The hypothesis holds that exposure to foreign antigens causes activation of T helper cells (subdivided into types 1 (Th1) and 2 (Th2)), which in turn causes inflammation. This is a major mechanism by which the body combats infection, but there may be faulty regulation of this Th1/Th2 system if there is lack of early childhood exposure to a variety of infections and other antigens, especially in the genetically susceptible. This could lead to excess activity of the Th2 system, which is important in many atopic conditions such eczema, asthma, and food allergy, or overexpression of the Th1 system, which is important in Crohn's disease (7) and multiple sclerosis (8). This hypothesis is plausible and is supported by immunologic data, but epidemiologic evidence of an association between a "hygienic" environment in early childhood and disease in later life is sparse and contradictory (9, 10).
The main problem with the paper by Green et al. (4) is that it evaluates exposure to a "hygienic" environment in the recent past and not in early childhood. Since the geographic areas chosen were small, current hygienic conditions will have correlated poorly with environmental conditions in the distant past. Furthermore, there is likely to have been considerable migration of individuals between these small geographic areas over time. Indeed, ecologic designs such as this one will not provide fruitful data on the hygiene hypothesis, because individuals are not identified and are a variety of ages. Therefore, the early childhood environment cannot be investigated, since there will not be a single time point that could be identified as representative of all individuals in a specified geographic area. This is not to say that GIS will have no role in evaluating the hygiene hypothesis. It is important to identify individual cases and controls, but it may be entirely appropriate to explore small geographic areas when assessing childhood exposure to a hygienic environment. This is arguably a more relevant assessment of exposure to a sanitized environment than evaluating how often an individual developed specific infections as a child or determining the socioeconomic status of his or her parents.
While I have issues with the inferences drawn from these data, important information is still present in the paper. IBD was more common in areas where there were fewer reports of enteric infection (4). This suggests that the current environment to which the gastrointestinal tract is exposed is associated with the development of chronic gastrointestinal disease. Since IBD is associated with multiple sclerosis, it is possible that a reduction in enteric infections may also be associated with diseases outside of the gastrointestinal tract. A finding of a negative association between multiple sclerosis incidence and enteric infections in a logistic regression model with multiple sclerosis used as the dependent variable would strengthen this hypothesis and highlights the possible role gastrointestinal flora may play in a wide variety of diseases. This is plausible, as there are more bacterial cells within the gut lumen than human cells in the entire body (11), and we human beings could be viewed simply as receptacles for our intestinal bacterial flora. Usually this coexistence is mutually beneficial, but subtle changes in gastrointestinal bacterial flora or exposure to mild pathogens may disturb immune function and lead to gastrointestinal, autoimmune, or allergic diseases. This is distinct from the hygiene hypothesis in that these changes can occur throughout life rather than just in early childhood (11). This is analogous to arguments between persons who believe that fetal environment is a key determinant of disease in later life (12) and those who take a life-course view of disease development (13). The data presented by Green et al. (4) support the concept that changes in gastrointestinal flora throughout life may play a role in a variety of diseases. It would be interesting to use the Manitoba database to study other systemic diseases that are thought to be immunologically mediated, such as asthma and insulin-dependent diabetes, to evaluate whether similar associations exist.
It is equally plausible that enteric infection is negatively associated with IBD because of residual confounding, particularly since the increase in relative risk is modest. Making causal inferences from associations is often problematic in epidemiology, and this is especially true of ecologic studies, as there is the added concern of the ecologic fallacy. This is less likely to occur when large numbers of small geographic areas are studied (14). However, this raises other issues, as the smaller the geographic area the less stable the estimate of disease incidence, particularly with a rare disease such as IBD. Because sparsely populated regions usually occupy a larger area, the least stable estimates can dominate the map visually and also make any disease associations inaccurate (15). Traditionally, this is overcome by the use of statistical techniques to smooth estimates in an effort to minimize random variation (16). This approach was taken by Green et al. (4), but an evaluation of hypothetical scenarios suggests that these techniques are not successful if the expected number of cases in each area is too small. For example, if the relative risk for an association is on the order of 2 (as in the case of the association between IBD and enteric infection), the expected number of cases in each area should be at least 20 (17). However, data from the study by Green et al. (4) suggest that the average expected number of cases of ulcerative colitis is six and that the expected number of cases of Crohn's disease is similar. It would be interesting to assess whether these findings are reproducible by other researchers, possibly studying larger geographic areas in a more populated location. It would also be useful to include a negative control disease in these studies. For example, findings of a negative association between enteric infections and IBD would be strengthened if there were no association with hemochromatosis (a liver disease that has a prevalence similar to that of IBD but is mainly genetically mediated).
GIS is a useful tool with which to measure associations between disease and the environment. As a gastroenterologist, I am particularly interested in the hypothesis that the gastrointestinal environment is important in the etiology of many immunologically mediated diseases. Infections such as cholera produce dramatic immediate effects and therefore are comparatively easy to study. Assessing the impact of subtle changes in gastrointestinal flora that may manifest as disease later in life is much more of a challenge, particularly since there are 1012 bacteria per gram of colonic contents. The creation of increasingly sophisticated databases with which to characterize the environment we live in and analysis of associations with a variety of diseases will provide valuable clues to the etiology of diseases, including those that might be caused by changes in gastrointestinal flora. The Winnipeg investigators are to be congratulated on having the vision and dedication to create such a database in Manitoba. The challenge is for others to do the same so that we can obtain a more global picture of how environment may influence disease. The notion that enteric infections may cause or contribute to a variety of immunologic diseases might seem fanciful, but so did John Snow's theories of cholera transmission in the 1850s. His mapping techniques had many deficiencies (18), but ultimately they led to the discovery of the infectious agent. GIS also has many weaknesses, but it too may play a vital role in our future understanding of how subtle changes in the environment cause disease.
 |
ACKNOWLEDGMENTS |
|---|
Dr. Moayyedi is a member of the speakers' bureau for AstraZeneca, Janssen-Ortho, and Altana, and his chair is funded in part by an unrestricted donation given to McMaster University by AstraZeneca.
|
References |
|---|
 TOP References |
|---|
- Cameron D, Jones IG. John Snow, the Broad Street pump and modern epidemiology. Int J Epidemiol 1983;12:393–6.
[Abstract/Free Full Text] - Vandenbroucke JP, Eelkman Rooda HM, Beukers H. Who made John Snow a hero? Am J Epidemiol 1991;133:967–73.
[Abstract/Free Full Text] - Rushton G. Public health, GIS, and spatial analytic tools. Annu Rev Public Health 2003;24:43–6.[CrossRef][Web of Science][Medline]
- Green C, Elliott L, Beaudoin C, et al. A population-based ecologic study of inflammatory bowel disease: searching for etiologic clues. Am J Epidemiol 2006;164:615–23.
[Abstract/Free Full Text] - Blanchard JF, Bernstein CN, Wajda A, et al. Small-area variations and sociodemographic correlates for the incidence of Crohn's disease and ulcerative colitis. Am Epidemiol 2001;154:328–35.[CrossRef]
- Strachan DP. Hay fever, hygiene, and the household size. BMJ 1989;299:1259–60.
[Free Full Text] - Wells RW, Blennerhassett MG. The increasing prevalence of Crohn's disease in industrialized societies: the price of progress? Can J Gastroenterol 2005;19:89–95.[Web of Science][Medline]
- Sospedra M, Martin R. Immunology of multiple sclerosis. Annu Rev Immunol 2005;23:683–747.[CrossRef][Web of Science][Medline]
- da Costa Lima R, Victora CG, Menezes AM, et al. Do risk factors for childhood infections and malnutrition protect against asthma? A study of Brazilian male adolescents. Am J Public Health 2003;93:1858–64.
[Abstract/Free Full Text] - Gibbs S, Surridge H, Adamson R, et al. Atopic dermatitis and the hygiene hypothesis: a case-control study. Int J Epidemiol 2004;33:199–207.
[Abstract/Free Full Text] - Macpherson AJ, Harris NL. Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol 2004;4:478–85.[CrossRef][Web of Science][Medline]
- Barker DJP. Mothers, babies and health in later life. New York, NY: Churchill Livingston, 1998.
- Kuh D, Davey Smith G. The life course and adult chronic disease: an historical perspective with particular reference to coronary artery disease. In: Kuh D, Ben-Shlomo Y, eds. A life course approach to chronic disease epidemiology. New York, NY: Oxford University Press, 1997:15–41.
- Briggs DJ, Elliott P. The use of geographical information systems in studies on environment and health. World Health Stat Q 1995;48:155–63.[Medline]
- Elliott P, Wartenberg D. Spatial epidemiology: current approaches and future challenges. Environ Health Perspect 2004;112:998–1006.[Web of Science][Medline]
- Elliott P, Martuzzi M. Spatial statistical methods in environmental epidemiology: a critique. Stat Methods Med Res 1995;4:137–59.
[Abstract/Free Full Text] - Richardson S, Thomson A, Best N, et al. Interpreting posterior relative risk estimates in disease mapping studies. Environ Health Perspect 2004;112:1016–25.[Web of Science][Medline]
- Lilienfeld DE. John Snow: the first hired gun? Am J Epidemiol 2000;152:4–9.
[Abstract/Free Full Text]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. Green, L. Elliott, C. Beaudoin, and C. N. Bernstein Green et al. Respond to "Clues to the Etiology of Inflammatory Bowel Disease" Am. J. Epidemiol., October 1, 2006; 164(7): 627 - 628. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||